Recent estimates show that over 50 million Americans have metabolic syndrome (MetS) and are at risk for developing cardiovascular disease and type-2 diabetes. Risk factors that contribute to MetS include atherogenic dyslipidemia and glucose intolerance. Many genes involved in dyslipidemia and glucose metabolism are regulated by modulation of the farnesoid X receptor (FXR). Xanthohumol (XN), the principal prenylflavonoid of hops (Humulus lupulus), modulates FXR and was shown to lower plasma triglycerides and glucose in a mouse model of MetS. Dietary XN supplements have recently become available on the market to 'improve general health', but little is known regarding their efficacy and safety in humans. Our long-term goal is to determine the health benefits of XN and related prenylflavonoids in humans. The objective of this application is to determine the effects of XN on triglyceride, cholesterol and glucose homeostasis in cultured hepatoma cells and in humans diagnosed with MetS. Our central hypothesis is that XN exerts its effects on lipid and glucose metabolism by modulation of FXR. The rationale for the proposed research is that successful completion of the studies will provide an assessment of the therapeutic potential of XN as a novel CAM modality in the treatment of MetS-related disorders. In Specific Aim 1, the overall effect of XN on triglyceride, cholesterol and glucose levels will be determined in HepG2 hepatoma cells. Our working hypothesis is that XN dose-dependently affects triglyceride, cholesterol, and glucose metabolism by modulation of FXR. In Specific Aim 2, the overall effect of XN on markers of MetS will be determined in humans. A double-blinded, randomized, placebo-controlled study of 36 subjects with diagnosed MetS will be conducted to determine safety and efficacy of XN at two doses (20 mg and 60 mg XN once/day) and the magnitude of the effect on the biomarkers will be related to steady-state plasma levels of XN and its metabolites. The clinical trial will be preceded by a single-dose pharmacokinetic (PK) study with the aim to determine PK parameters and to calculate steady-state plasma XN levels for each of the human subjects. The proposed research in innovative, because XN has not previously been evaluated as a biologically active agent in the amelioration of MetS in humans. Human data are urgently needed in view of the fact that thousands of Americans are consuming XN supplements over prolonged periods of time without knowledge of XN's efficacy and safety. PUBLIC HEALTH RELEVANCE: Thousands of Americans are taking dietary supplements containing xanthohumol (XN), a prenylflavonoid from hops (Humulus lupulus), for improving general health, but XN's safety and efficacy have not been investigated in humans. As a modulator of the farnesoid X receptor, XN could be an attractive natural product for the complementary treatment of metabolic syndrome-related disorders and could provide an alternative for currently used antihyperlipidemics and antiglycemics, especially for patients that do not tolerate drugs in these therapeutic classes.